The epidermal growth factor receptor (EGFR) is a 170 kDa type I transmembrane protein and is known to be overexpressed in many human tumors, e.g., carcinoma of the lung, breast, colon, stomach, brain, bladder, head, neck, ovaries and prostate. Its overexpression is frequently accompanied by the production of EGFR-ligands, TGF-α (transforming growth factor-α) and EGF (epidermal growth factor), and the binding of the ligands to EGFR was confirmed to induce cell proliferation and tumor growth. Blocking the interaction between such ligands and EGFR using an antibody against EGFR therefore can inhibit tumor growth, which has been proven effective by experiments that employed monoclonal antibodies against EGFR.
Antibody C225 (trade name: Erbitux; ImClone, U.S), which is currently used in clinical trials for the treatment of metastatic colorectal cancers, is a chimeric antibody, comprising the mouse antibody variable regions linked to human antibody IgG1 constant regions (about 30% of mouse amino acid sequence is included therein). C225 has been shown to inhibit tumor cell growth, EGFR phosphorylation in vitro and tumor formation in a nude mouse, and also to completely eradicate human tumor xenografts in mice when used together with a specific chemotherapeutic agent. However, the antibody has the problem of inducing immune reactions in some (˜10%) of the patients treated therewith. Accordingly, there exists a need for improved therapeutic antibodies against EGFR.
Therapeutic agents for target therapy constitute about 50% of anticancer drugs recently approved by U.S. Food and Drug Administration (FDA). Such antibodies provide target specificity and a capability to effectively engage the immune system, which in combination with long biological half-lives thereof have alerted researchers to the therapeutic potentials thereof. As a result, the U.S. FDA has recently approved the use of several antibodies for cancer treatment. Antibodies play prominent roles in many therapeutic approaches to diseases, which has become even more attractive with the recent advent of technologies that allow the development of fully human antibodies.
The present inventors have endeavored to develop novel, improved antibodies having new complementarity determining regions (CDRs) and have found that such antibodies can be used in cancer treatment by blocking the EGFR-mediated signal transduction.